The overall goal of this project is to understand immune regulatory networks and pathways that control inflammation and antiviral immune responses in HIV-infected individuals on antiretroviral therapy (ART). Despite ART, chronic inflammation continues to be a hallmark of HIV infection that predicts disease progression and other adverse outcomes. In preliminary studies, we identified monocyte transcriptome signatures that predict protective antiviral responses versus nonprotective inflammatory responses during treatment interruption in HIV-infected individuals. We then used bioinformatic software to predict immune networks and inflammatory pathways linked to differences in inflammatory cytokine production and clinical outcomes. We hypothesize that circulating microbial products due to a leaky damaged gut, in combination with specific proinflammatory cytokines, PD1/PDL-1, and other as yet unknown host factors, promote inflammation and dysfunctional immune responses in HIV-infected individuals on ART through monocyte-driven pathways that control the balance between inflammatory versus antiviral responses. Cocaine alters these pathways by modulating the IDO/tryptophan metabolism pathway and innate immune responses, promoting pathological inflammation, dysfunctional innate immune responses, and HIV replication. To investigate this hypothesis, we will use systems biology approaches to analyze large-scale clinical, biological, and 'omics datasets from HIV-infected subjects with different clinical outcomes. Integrative analysis, network perturbations, and targeted experimentation will be used to computationally build models of networks and pathways that control inflammatory versus antiviral responses. These studies will provide insights into mechanisms that control inflammation and immune responses, which may be helpful for development of new therapeutic strategies to improve clinical outcomes in HIV-infected populations. PUBLIC HEALTH RELEVANCE: This project will use large-scale clinical and biological datasets, computational modeling, and systems biology approaches to identify key regulatory networks and pathways that control the balance between protective antiviral immune responses versus nonprotective inflammatory responses in HIV-infected individuals on antiretroviral therapy. These studies will provide insights into mechanisms that control inflammation and immune responses, which may be helpful for development of new therapeutic strategies to improve clinical outcomes in HIV-infected populations. The studies will also provide a better understanding of mechanisms by which substance abuse, in particular crack cocaine, might adversely affect inflammatory pathways and immune responses in HIV-infected populations.